KEAP1 – Non-Small Cell Lung Carcinoma

KEAP1 encodes Kelch-like ECH-associated protein 1, a substrate adaptor for the CUL3 ubiquitin ligase complex that targets NRF2 for proteasomal degradation. Under oxidative or chemotherapeutic stress, loss-of-function mutations or epigenetic silencing of KEAP1 lead to constitutive activation of NRF2 and upregulation of cytoprotective gene programs. Early sequencing studies identified KEAP1 mutations in resected Stage I–II NSCLC, prompting investigation of its role as a prognostic and predictive biomarker in non-small cell lung carcinoma (PMID:20213688).

Somatic mutational analyses across multiple cohorts consistently detect KEAP1 alterations in 5–15% of NSCLC cases. In a retrospective series of 79 resected Stage I–II tumors, 4/79 (5.1%) harbored KEAP1 mutations, correlating with a lower 5-year overall survival (25% vs. 76%; P = 0.038) and reduced disease-free interval (PMID:20213688). In a US clinico-genomic database of 703 advanced squamous NSCLC, 31.6% of patients carried NFE2L2 and/or KEAP1 mutations, with the KEAP1-mutant subgroup showing shorter real-world progression-free survival (4.54 vs. 6.25 months; P = .003) and overall survival (13.59 vs. 17.37 months; P = .4105) on first-line therapy (PMID:35705448). In a cohort of 6297 NSCLC patients, KEAP1 mutations remained an independent negative prognostic factor in both localized (HR = 1.68; P = 0.001) and advanced-stage tumors (HR = 1.40; P < 0.001) (PMID:34601169).

The spectrum of KEAP1 alterations in NSCLC includes missense substitutions, truncating mutations, loss of heterozygosity, and promoter hypermethylation. Promoter methylation was detected in 22/47 (47%) NSCLCs, somatic mutations in 7/47 (15%), and loss of heterozygosity in 10/47 (21%), with double-hit events predicting worse progression (HR = 3.62; P = 0.02) (PMID:21610322). One recurrent variant, c.730G>A (p.Glu244Lys), was identified in a plasma NGS assay of an ALK-rearranged lung adenocarcinoma, where it associated with intrinsic resistance to ALK TKI and chemotherapy (PMID:39522087).

Functional studies reveal that cancer-derived KEAP1 mutations disrupt NRF2 binding or degradation. Hypomorphic “super-binder” mutants (e.g., p.Arg320Gln, p.Arg470Cys) retain NRF2 ubiquitination but fail to promote its proteasomal turnover, leading to NRF2 stabilization and nuclear accumulation (PMID:24322982). Structural and biophysical analyses of the Keap1–Nrf2 interaction map critical sensor motifs (DLG and ETGE) and show that mutations in these degrons abrogate the hinge-and-latch mechanism required for NRF2 degradation (PMID:24366543).

Clinically, KEAP1 mutation or epigenetic inactivation confers chemoresistance and radioresistance in NSCLC. KEAP1- or NFE2L2-mutant localized tumors exhibit higher local recurrence after radiotherapy but not surgery, and glutaminase inhibition restores radiosensitivity in KEAP1-deficient models (PMID:33071215). In EGFR-mutated NSCLC, co-mutation of KEAP1/NFE2L2/CUL3 significantly reduces time to EGFR-TKI treatment failure (4.7 vs. 13.0 months; P = 0.0014) (PMID:31319993). These findings support KEAP1 status as a predictive biomarker for therapeutic stratification.

Integration of genetic and functional data establishes a Strong association between somatic KEAP1 alterations and NSCLC outcomes, driven by recurrent deleterious variants in multiple independent cohorts and concordant mechanistic studies. Additional real-world and prospective trials will further refine the predictive utility of KEAP1 as a biomarker. Key Take-home: KEAP1 mutation or silencing defines a molecular NSCLC subset with NRF2-driven chemoresistance and poorer survival, warranting routine genomic testing and exploration of NRF2-targeted therapies.

References

• Journal of surgical oncology • 2010 • Mutations in Keap1 are a potential prognostic factor in resected non-small cell lung cancer. PMID:20213688
• Clinical lung cancer • 2022 • Survival Outcomes and Treatment Patterns in Patients With NFE2L2 and/or KEAP1 Mutation-Positive Advanced Squamous Cell NSCLC Using a Real-World Clinico-Genomic Database. PMID:35705448
• Journal of thoracic oncology • 2022 • Comprehensive Analysis of TP53 and KEAP1 Mutations and Their Impact on Survival in Localized- and Advanced-Stage NSCLC. PMID:34601169
• Epigenetics • 2011 • Frequent epigenetics inactivation of KEAP1 gene in non-small cell lung cancer. PMID:21610322
• Cancer research • 2014 • Cancer-derived mutations in KEAP1 impair NRF2 degradation but not ubiquitination. PMID:24322982
• Molecular and cellular biology • 2014 • Kinetic, thermodynamic, and structural characterizations of the association between Nrf2-DLGex degron and Keap1. PMID:24366543
• Cancer discovery • 2020 • KEAP1/NFE2L2 Mutations Predict Lung Cancer Radiation Resistance That Can Be Targeted by Glutaminase Inhibition. PMID:33071215
• Lung cancer (Amsterdam, Netherlands) • 2019 • Impact of KEAP1/NFE2L2/CUL3 mutations on duration of response to EGFR tyrosine kinase inhibitors in EGFR mutated non-small cell lung cancer. PMID:31319993

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